The muscular dystrophies are complex genetic diseases characterized by inherited or sporadic defects in genes that encode muscle proteins. Although Duchenne (DMD), Becker, limb girdle, congenital, facioscapulohumeral, myotonic, oculopharyngeal, distal, and Emery-Dreifuss are the most common muscular dystrophies, the total number of diseases characterized as muscular dystrophies exceeds thirty (MD-CARE_Act, 2008). Common to all of the muscular dystrophies is progressive skeletal muscle weakness and the death of muscle cells and tissue. Although the genetic basis for most of the dystrophies is known, a disease cure may still be years away. This fact has increased the research priority mandate from researchers, family support organizations (G[unreadable]nter Scheuerbrandt, 2008) and the government (MD-CARE_Act, 2008) to identify critical "downstream" events in the dystrophic process that can be therapeutically targeted to halt or slow the disease progression until a genetic (gene therapy) cure is realized. Transforming Growth Factor beta (TGF-() signaling is pathogenic in dystrophy (Chen et al., 2005). Recent work by our group showed that antagonizing TGF-( normalizes muscle repair and restores muscle function in the well-described mdx mouse model of muscular dystrophy (Cohn et al., 2007). To identify critical downstream transcriptional events following increased TGF-( signaling, we generated a tet-repressible muscle-specific TGF-( transgenic mouse and we find that over-expression of TGF-( causes muscle weakness (Hoffman and Chen, unpublished). In related preliminary studies examining gene expression in clinical DMD muscle biopsy samples we show that the truncated form of the Brain-derived Neurotrophic Factor (BDNF) receptor, trkB.T1, but not other trkB isoforms, is highly associated with TGF-( expression (Hoffman et al., unpublished). Further investigation revealed that genetic deletion of trkB.T1 (Dorsey et al., 2006) results in a gain-of-function in neuromuscular performance, increased muscle contractility and resistance to eccentric muscle injury (Dorsey and Ward, unpublished). Complementary gene expression studies showed that TGF-( and its receptor were downregulated in trkB.T1-/- muscle. An intercross between trkB.T1-/- and mdx mice to reduce trkB.T1 expression in vivo resulted in a complete rescue of dystrophy-associated loss of skeletal muscle contractility (Dorsey and Ward, unpublished), similar to targeting TGF-( (Cohn et al., 2007). We hypothesize that trkB.T1 may be a significant disease modifier of muscular dystrophy and could represent a novel therapeutic target for its treatment. PUBLIC HEALTH RELEVANCE: Muscular dystrophy is a disease that causes significant muscle weakness that gets worse over time. Although we know about the genetic causes of the disease, we still do not have ways to slow down muscle weakness or make muscles stronger once they become weak. From our preliminary studies, we have an idea that two molecules that function in muscle cells to regulate muscle strength might be able to be manipulated to improve muscle function in patients with muscular dystrophy. This study will try to figure out why these two molecules may be possible therapeutic targets. Our goal is to prevent, improve, or restore muscle function in patients with muscular dystrophy.